Neutrophil extracellular traps in influenza infection.

Despite recent progress in developing novel therapeutic approaches and vaccines, influenza is still considered a global health threat, with about half a million mortality worldwide. This disease is caused by Influenza viruses, which are known for their rapid evolution due to different genetical mechanisms that help them develop new strains with the ability to evade therapies and immunization. Neutrophils are one of the first immune effectors that act against pathogens. They use multiple mechanisms, including phagocytosis, releasing the reactive oxygen species, degranulation, and the production of neutrophil extracellular traps. Neutrophil extracellular traps are used to ensnare pathogens; however, their dysregulation is attributed to inflammatory and infectious diseases. Here, we discuss the effects of these extracellular traps in the clinical course of influenza infection and their ability to be a potential target in treating influenza infection.

Notch signaling pathway: a comprehensive prognostic and gene expression profile analysis in breast cancer.

Breast cancer is a complex disease exhibiting a great degree of heterogeneity due to different molecular subtypes. Notch signaling regulates the differentiation of breast epithelial cells during normal development and plays a crucial role in breast cancer progression through the abnormal expression of the Notch up-and down-stream effectors. To date, there are only a few patient-centered clinical studies using datasets characterizing the role of Notch signaling pathway regulators in breast cancer; thus, we investigate the role and functionality of these factors in different subtypes using publicly available databases containing records from large studies. High-throughput genomic data and clinical information extracted from TCGA were analyzed. We performed Kaplan-Meier survival and differential gene expression analyses using the HALLMARK_NOTCH_SIGNALING gene set. To determine if epigenetic regulation of the Notch regulators contributes to their expression, we analyzed methylation levels of these factors using the TCGA HumanMethylation450 Array data. Notch receptors and ligands expression is generally associated with the tumor subtype, grade, and stage. Furthermore, we showed gene expression levels of most Notch factors were associated with DNA methylation rate. Modulating the expression levels of Notch receptors and effectors can be a potential therapeutic approach for breast cancer. As we outline herein, elucidating the novel prognostic and regulatory roles of Notch implicate this pathway as an essential mediator controlling breast cancer progression.

The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)?

Autophagy plays a critical role in balancing sources of energy in response to harsh conditions and nutrient deprivation. Autophagy allows cells to survive in harsh condition and also serve as a death mechanism. Any dysregulation in autophagy signaling may lead to several disorders. Autophagy has been proposed to explain chemotherapy resistance in acute myeloid leukemia (AML). This signaling pathway can either act as a tumor suppressive function or chemo-resistance mechanism. Conventional chemotherapy drugs enhance apoptosis and indicate clinical benefit, but in some cases, relapse and chemotherapy resistance are observed. In leukemia, autophagy may promote cell survival in response to chemotherapy drugs. Therefore, new strategies by inhibiting or activating autophagy may find a broad application for treating leukemia and may significantly enhance clinical outcomes. In this review, we discussed the dimensional role of autophagy in leukemia.

Effects of different autophagy inhibitors on sensitizing KG-1 and HL-60 leukemia cells to chemotherapy.

A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well-known inhibitors of autophagy (as 3-MA, BafA1, and HCQ) in leukemia KG-1 and HL-60 cells exposed to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC-3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG-1 cells compared to HL-60 cell line. This study showed the involvement of autophagy during the treatment of KG-1 and HL-60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG-1 cells.

Curcumin Combined with Thalidomide Reduces Expression of STAT3 and Bcl-xL, Leading to Apoptosis in Acute Myeloid Leukemia Cell Lines.

INTRODUCTION: Acute myeloid leukemia (AML) is a type of blood disorder that exhibits uncontrolled growth and reduced ability to undergo apoptosis. Signal transducer and activator of transcription 3 (STAT3) is a family member of transcription factors which promotes carcinogenesis in most human cancers. This effect on AML is accomplished through deregulation of several critical genes, such as B cell lymphoma-extra-large (BCL-XL) which is anti-apoptotic protein. The aim of this study was to evaluate the effect of curcumin (CUR) and thalidomide (THAL) on apoptosis induction and also the alteration of the mRNA expression level of STAT3 and BCL-XL mRNA on AML cell line compounds. METHODS: The growth inhibitory effects of CUR and THAL and their combination were measured by MTT assay in U937 and KG-1 cell lines. The rates of apoptosis induction and cell cycle analysis were measured by concurrent staining with Annexin V and PI. The mRNA expression level of STAT3 and BCL-XL was evaluated by Real-Time PCR. RESULTS: CUR inhibited proliferation and induced apoptosis in both KG-1 and U937 cells and this effect increased by combination with THAL. The expression level of STAT3 and BCL-XL was significantly down-regulated in KG-1 cells after treatment by CUR and THAL and their combination. CONCLUSION: Overall, our findings suggested that down-regulation of STAT3 and BCL-XL mRNA expression in response to CUR and THAL treatment lead to inhibition of cell growth and induction of apoptosis.

Arsenic Trioxide and Thalidomide Combination Induces Autophagy Along with Apoptosis in Acute Myeloid Cell Lines.

OBJECTIVE: Autophagy and apoptosis play key roles in cancer survival and pathogenesis and are governed by specific genes which have a dual role in both cell death and survival. Arsenic trioxide (ATO) and thalidomide (THAL) are used for treatment of many types of hematologic malignancies. ATO prevents the proliferation of cells and induces apoptosis in some cancer cells. Moreover, THAL has immunomodulatory and antiangiogenic effects in malignant cells. The aim of present study was to examine the effects of ATO and THAL on U937 and KG-1 cells, and evaluation of mRNA expression level of VEGFs genes, PI3K genes and some of autophagy genes. MATERIALS AND METHODS: In this in vitro experimental study, U937 and KG-1 cells were treated by ATO (0.4-5 µM) and THAL (5-100 µM) for 24, 48 and 72 hours. Cell viability was measured by MTT assay. The apoptosis rate and cell cycle arrest were evaluated by flow cytometry (Annexin/PI) and cell cycle flow cytometry analysis, respectively. The effect of ATO/THAL on mRNAs expression was evaluated by real-time polymerase chain reaction (PCR). RESULTS: ATO/THAL combination enhanced cell apoptosis in a dose-dependent manner. Also, ATO/THAL induced SubG1/ G1 phase arrest. mRNA expression levels of VEGFC (contrary to other VEGFs isoform), PI3K, AKT, mTOR, MEK1, PTEN, IL6, LC3 and P62 genes were upregulated in acute myeloid leukemia (AML) cells following treatment with ATO/THAL. CONCLUSION: Combined treatment with ATO and THAL can inhibit proliferation and invasion of AML cells by down-regulating ULK1 and BECLIN1 and up-regulating PTEN and IL6, and this effect was more marked than the effects of ATO and THAL alone.

Effects of Sorafenib and Arsenic Trioxide on U937 and KG-1 Cell Lines: Apoptosis or Autophagy?

OBJECTIVE: Acute myeloid leukemia (AML) is a clonal disorder of hemopoietic progenitor cells. The Raf serine/threonine (Ser/Thr) protein kinase isoforms including B-Raf and RAF1, are the upstream in the MAPK cascade that play essential functions in regulating cellular proliferation and survival. Activated autophagy-related genes have a dual role in both cell death and cell survival in cancer cells. The cytotoxic activities of arsenic trioxide (ATO) were widely assessed in many cancers. Sorafenib is known as a multikinase inhibitor which acts through suppression of Ser/Thr kinase Raf that was reported to have a key role in tumor cell signaling, proliferation, and angiogenesis. In this study, we examined the combination effect of ATO and sorafenib in AML cell lines. MATERIALS AND METHODS: In this experimental study, we studied in vitro effects of ATO and sorafenib on human leukemia cell lines. The effective concentrations of compounds were determined by MTT assay in both single and combination treatments. Apoptosis was evaluated by annexin-V FITC staining. Finally, mRNA levels of apoptotic and autophagy genes were evaluated using real-time polymerase chain reaction (PCR). RESULTS: Data demonstrated that sorafenib, ATO, and their combination significantly increase the number of apoptotic cells. We found that the combination of ATO and sorafenib significantly reduces the viability of U937 and KG-1 cells. The expression level of selective autophagy genes, ULK1 and Beclin1 decreased but LC3-II increased in U937. CONCLUSION: The expression levels of apoptotic and autophagy activator genes were increased in response to treatment. The crosstalk between apoptosis and autophagy is a complicated mechanism and further investigations seem to be necessary.

Phytochemicals as potent modulators of autophagy for cancer therapy.

The dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, and accordingly universal research efforts have focused on exploring novel compounds with autophagy-modulating properties. While a number of synthetic autophagy modulators have been identified as promising cancer therapy candidates, autophagy-modulating phytochemicals have also attracted attention as potential treatments with minimal side effects. In this review, we firstly highlight the importance of autophagy and its relevance in the pathogenesis and treatment of cancer. Subsequently, we present the data on common phytochemicals and their mechanism of action as autophagy modulators. Finally, we discuss the challenges associated with harnessing the autophagic potential of phytochemicals for cancer therapy.

A Comprehensive Review on Pharmacotherapeutics of Three Phytochemicals, Curcumin, Quercetin, and Allicin, in the Treatment of Gastric Cancer.

OBJECTIVE: Gastric cancer is one of the most common causes of cancer-related death worldwide. Medicinal plants are one of the main sources for discovery of new pharmacological agents especially for treatment of cancers. The aim of the present study is to review pharmacotherapeutic aspects of three mostly studied phytochemicals including curcumin, quercetin, and allicin for management of gastric cancer. METHODS: Scopus, PubMed, Web of Science, and Google Scholar were searched for the effects of curcumin, quercetin, allicin, and their analogs in gastric cancer. Data were collected up to November 2015. The search terms were "curcumin," "quercetin," "allicin," and "gastric cancer" or "cancer." RESULTS: Curcumin demonstrated anti-angiogenic, anti-proliferative, anti-metastatic, pro-apoptotic, and anti-helicobacter activities. Quercetin inhibited cell growth and induced apoptosis, necrosis, and autophagy as well as anti-Helicobacter activity. Allicin showed apoptotic and anti-Helicobacter properties. All three natural compounds had low bioavailability. CONCLUSIONS: Although preclinical studies demonstrated the activity of curcumin, quercetin, and allicin in gastric cancer, clinical trials are needed to confirm their effectiveness. Applying their possible synergistic action and suitable drug delivery system in clinical studies can be also an attractive approach with the purpose of finding new extremely efficient anti-gastric cancer agents. Curcumin, quercetin, and allicin seem to be good candidates for management of gastric cancer through their pro-apoptotic, anti-proliferative, and anti-helicobacter activities.

Anti-Vascular Endothelial Growth Factor Effects of Sorafenib and Arsenic Trioxide in Acute Myeloid Leukemia Cell Lines

Acute myeloid leukemia (AML), is a clonal disorder caused by acquired somatic mutations and chromosomal rearrangements. According to some evidence, progression of hematolymphoid malignancies depends on the induction of new blood vessel formation under the influence of acute leukemia. Various factors are produced by cancer cells under hypoxic conditions to increase vascular formation. Among these, vascular endothelial growth factor (VEGF) plays a crucial role. Cytotoxicity and anticancer effects of arsenic trioxide (ATO) have been reported in many cancers. Sorafenib, known as an angiogenic inhibitor, decreases leukemic cell survival. The aim of this study was to indicate combination effects of ATO and sorafenib in two AML cell lines, KG-1 and U937. Effective doses was determined by MTT assay for both single and combination treatments. Percentages of apoptotic cells were evaluated by Annexin V FITC staining and mRNA levels of VEGF isoforms and receptor expression were investigated by Real-Time PCR. Our data show that sorafenib (5µM and 7µM in KG-1 and U937 cell lines respectively), ATO (1.618µM and 1µM in KG-1 and U937 cell lines respectively), and also their combination significantly increased the percentage of apoptotic cells. In addition the mRNA level of VEGF isoforms was downregulated in the U937 cell line while upregulated in KG-1 cells. Taken together, our results suggest that the VEGF autocrine loop may have an influence on AML development and progression and could be consider as a therapeutic target. The combination of sorafenib as a VEGF inhibitor with ATO synergistically inhibits cell proliferation and promotes apoptosis.